BACKGROUND: Abnormal angiogenesis can induce hypoxia within a highly proliferating tumor mass, and these hypoxic conditions can in turn create clinical problems, such as resistance to chemotherapy. However, the mechanism by which hypoxia induces these changes has not yet been determined. Therefore, this study was conducted to determine how hypoxia induces changes in cell viability and extracellular microenvironments in an in vitro culture system using non-small cell lung cancer cells. METHODS: The non-small cell lung cancer cell line, A549 was cultured in DMEM or RPMI-1640 media that contained fetal bovine serum. A decrease in the oxygen tension of the media that contained the culture was then induced in a hypoxia microchamber using a CO2-N2 gas mixture. A gas analysis and an MTT assay were then conducted. RESULTS: (1) The decrease in oxygen tension was checked the anaerobic gas mixture for 30 min and then reoxygenation was induced by adding a 5% CO2-room air gas mixture to the chamber. (2) Purging with the anaerobic gas mixture was found to decrease the further oxygen tension of cell culture media. (3) The low oxygen tension resulted in a low pH, lactic acidosis and a decreased glucose concentration in the media. (4) The decrease in glucose concentration that was observed as a result of hypoxia was markedly different when different types of media were evaluated. (5) The decrease in oxygen tension inhibited proliferation of A549 cells. CONCLUSION: These data suggests that tumor hypoxia is associated with acidosis and hypoglycemia, which have been implicated in the development of resistance to chemotherapy and radiotherapy.
Acidosis ; Acidosis, Lactic ; Anoxia ; Carcinoma, Non-Small-Cell Lung* ; Cell Culture Techniques ; Cell Line* ; Cell Proliferation* ; Cell Survival ; Drug Therapy ; Glucose ; Hydrogen-Ion Concentration ; Hypoglycemia ; Oxygen* ; Radiotherapy

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T_1/2), area under the curve (AUC), time to reach maximum concentration (T_max). Compared with the control group, AUC was increased by 23.5%, T_max and T_1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Metformin/therapeutic use* ; Acidosis, Lactic ; Tandem Mass Spectrometry ; Hypoxia ; Glucose

Nucleoside reverse transcriptase inhibitors (NRTIs), which are used for the treatment of human immunodeficiency virus (HIV) infection have been associated with a wide spectrum of clinical manifestations, including hepatic steatosis, lipodystrophy, myopathy, and lactic acidosis. Such adverse effects are postulated to result from the inhibition of mitochondrial DNA gamma polymerase, which causes the depletion of mitochondrial DNA and eventual the disruption of oxidative phosphorylation. Although cases of severe decompensated lactic acidosis are rare, this syndrome is associated with a high mortality rate. We report upon the first Korean case, of severe lactic acidosis in an acquired immunodeficiency syndrome (AIDS) patient receiving stavudine, an anti-HIV drug.
Acidosis, Lactic/*chemically induced ; Acquired Immunodeficiency Syndrome/*drug therapy ; Adult ; Anti-HIV Agents/*adverse effects/therapeutic use ; Female ; Human ; Sodium Bicarbonate/therapeutic use ; Stavudine/*adverse effects/therapeutic use

Because of the widespread use of ant-obesity medications, bariatricians need to be aware not only of common adverse events but also uncommon serious events in the pharmacotherapy of obesity. Safety and tolerability must be considered in selecting the drug, titrating the dosage, and monitoring patients. In Korea, orlistat and lorcaserine are the two anti-obesity drugs that can be used for long-term treatment, and in the US, liraglutide, phentermine/topiramate, and naltrexone/bupropion have been recently approved. In general, all of these drugs have very good safety and tolerability profiles. Common adverse events of these drugs are well understood, and they can be coped with or prevented by adjusting the dosage properly. In addition, patients can recover from serious events by stopping the medication. However, there are other serious side effects that need to be monitored for. These include liver injury, acute kidney injury, and pancreatitis for orlistat; valvulopathy for lorcaserine; thyroid C-cell pathology and pancreatitis for liraglutide; metabolic acidosis, urolithiasis, acute angle closure glaucoma, and teratogenic effects for phentermine/topiramate; and severe nausea and heart disease for naltrexone/bupropion.
Acidosis ; Acute Kidney Injury ; Anti-Obesity Agents ; Drug Therapy ; Glaucoma, Angle-Closure ; Heart Diseases ; Humans ; Korea ; Liver ; Liraglutide ; Nausea ; Obesity ; Pancreatitis ; Pathology ; Thyroid Gland ; Urolithiasis

To establish rat model of lung ischemia/reperfusion (IR) in vivo, and to explore the effects of acidification pretreatment for respiratory acidosis on the expression of matrix metalloproteinase-9 (MMP-9) and the possible mechanisms.
 Methods: A total of 36 male Sprague-Dawley rats were divided into a sham group (S group), a IR group, and an experiment group (RA group) (n=12 in each group). The rat left lung hilum in the S group was dissociated, followed by perfusion without ischemia. After the left lung hilum in the IR group was blocked for 45 min, the rats were followed by reperfusion for 180 min. After left lung hilum in the RA group was dissociated, the respiratory parameters were adjusted so that pressure of end tidal carbon dioxide (PETCO2) reached 56-65 mmHg (1 mmHg=0.133 kPa) for 5 min, then the rats was subjected to IR. Lung tissue wet/dry (W/D) and lung permeability index (LPI) were calculated, while the lung histopathology was observed and the MMP-9 protein expression were measured.
 Results: Compared with the control group, the W/D and LPI in the IR group and the RA group increased after reperfusion (both P<0.05), and the levels of W/D and LPI in the group RA were lower than that in the IR group (P<0.05). LPI and pathology scores were significantly lower in the RA group than those in the IR group (both P<0.01). After IR, the expression of MMP9 in the lung tissues in the IR group and the RA group increased significantly (both P<0.01). The expression of MMP-9 protein in the RA group was significantly lower than that in the IR group (P<0.01).
 Conclusion: After lung IR injury, the expression of MMP-9 protein, vascular permeability and inflammatory exudation is increased. The acidification pretreatment for respiratory acidosis can inhibit the expression of MMP-9 protein and reduce inflammatory exudation after lung IR, showing a protective effect on lung IR injury.
Acidosis, Respiratory ; drug therapy ; prevention & control ; Animals ; Gene Expression Regulation, Enzymologic ; drug effects ; Lung ; enzymology ; Lung Injury ; enzymology ; Male ; Matrix Metalloproteinase 9 ; genetics ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; drug therapy ; prevention & control

No abstract available.
Acidosis/*complications/drug therapy ; Acidosis, Renal Tubular/drug therapy/etiology/metabolism/*pathology ; Adult ; Aquaporin 2/analysis ; Biological Markers/analysis ; Biopsy ; Female ; Humans ; Immunohistochemistry ; Kidney Tubules/chemistry/drug effects/*pathology ; Nephrocalcinosis/etiology/pathology ; Proton-Translocating ATPases/analysis ; Sodium Bicarbonate/therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome

Metabolic acidosis is a cause of renal disease progression, and alkali therapy ameliorates its progression. However, there are few reports on the role of renal acid-base transporters during alkali therapy. We evaluated the effect of sodium bicarbonate therapy and the role of acid-base transporters on renal disease progression in rats with a remnant kidney. Sprague-Dawley rats consumed dietary sodium bicarbonate (NaHCO3) or sodium chloride (NaCl) with 20% casein after a 5/6 nephrectomy. After being provided with a casein diet, the NaHCO3-treated group had higher levels of serum bicarbonate than the control group. At week 4, the glomerular filtration rate in the NaHCO3 group was higher than that in the NaCl group, and the difference became prominent at week 10. The glomerulosclerosis and tubulointerstitial damage indices in the NaHCO3 group were less severe compared with controls at week 4 and 10. The expression of the Na/H exchanger (NHE) was decreased, and apical reactivity was decreased in the NaHCO3 group, compared with the NaCl group. Endothelin-1 levels in the kidney were also decreased in the NaHCO3 group. Dietary sodium bicarbonate has the effects of ameliorating renal disease progression, which may be related to the altered expression of NHE in the remaining kidney.
Acidosis/*drug therapy ; Alkalies/*therapeutic use ; Animals ; Caseins/administration & dosage ; Disease Progression ; Glomerular Filtration Rate/drug effects ; Glomerulosclerosis, Focal Segmental/drug therapy ; Kidney/injuries ; Male ; Nephrectomy ; Nephritis, Interstitial/drug therapy ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/*drug therapy ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/administration & dosage ; Sodium-Hydrogen Antiporter/*antagonists & inhibitors

Metabolic and electrolyte abnormalities, including hypokalemia, hyperglycemia and lactic acidosis, are associated with theophylline overdose. However, we report an unusual case of sinus tachycardia, lactic acidosis, hypokalemia and hyperglycemia associated with the usual theophylline dose in a patient with asthma. The theophylline dose was 200 mg orally twice daily. Three hours after administration of the third dose, the patient experienced palpitation. An electrocardiogram showed a sinus tachycardia. Arterial blood gas analysis revealed a mixed metabolic acidosis and respiratory alkalosis. Serum lactate level was 51 mmol/L (normal 0.7~2.1 mmol/L). Biochemistry results were sodium 136 mEq/L, chloride 99 mEq/L, potassium 1.9 mEq/L and glucose 204 mg/dL. Our case suggests that a possibility of theophylline-associated metabolic abnormalities should be considered when an asthmatic patient given the usual theophylline dose presents with lactic acidosis, hypokalemia and hyperglycemia of unknown etiology.
Acidosis, Lactic/*chemically induced ; Adult ; Asthma/drug therapy ; Bronchodilator Agents/administration & dosage/*adverse effects ; Case Report ; Female ; Human ; Hyperglycemia/chemically induced ; Hypokalemia/etiology ; Tachycardia, Sinus/chemically induced ; Theophylline/administration & dosage/*adverse effects

Fanconi syndrome (FS) is a rare condition that is characterized by defects in the proximal tubular function. A 48-year-old woman was admitted for evaluation of proteinuria. The patient showed normal anion gap acidosis, normoglycemic glycosuria, hypophosphatemia, and hypouricemia. Thus, her condition was compatible with FS. The M peak was found behind the beta globulin region in urine protein electrophoresis. Upon bone marrow examination, we found that 24% of cells were CD138+ plasma cells with kappa restriction. From a kidney biopsy, we found crystalline inclusions within proximal tubular epithelial cells. Thereafter, she was diagnosed with FS accompanied by multiple myeloma. The patient received chemotherapy and autologous stem cell transplantation, and obtained very good partial hematologic response. However, proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation. In short, we report a case of FS accompanied by multiple myeloma, demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy.
Acid-Base Equilibrium ; Acidosis ; Beta-Globulins ; Biopsy ; Bone Marrow Examination ; Crystallins ; Drug Therapy ; Electrophoresis ; Epithelial Cells ; Fanconi Syndrome* ; Female ; Glycosuria ; Humans ; Hypophosphatemia ; Immunoglobulin kappa-Chains ; Kidney ; Middle Aged ; Multiple Myeloma* ; Plasma Cells ; Proteinuria ; Stem Cell Transplantation

An overdose of antihypertensive agents, such calcium channel blockers (CCBs) and angiotensin II receptor blocker (ARBs), and the antihyperglycemic agent, metformin, leads to hypotension and lactic acidosis, respectively. A 40-year-old hypertensive and diabetic man with hyperlipidemia and a weight of 110 kg presented to the emergency room with vomiting, dizziness, and hypotension following an attempted drug overdose suicide with combined CCBs, ARBs, 3-hydroxy-3-methylglutaryl-coemzyme A reductase inhibitors, and metformins. A conventional medical treatment initially administered proved ineffective. The treatment was then changed to simultaneous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), which was effective. This shows that simultaneous ECMO and CRRT can be an effective treatment protocol in cases of ineffective conventional medical therapy for hypotension and lactic acidosis due to an overdose of antihypertensive agents and metformin, respectively.
Acidosis, Lactic ; Adult ; Antihypertensive Agents ; Calcium Channel Blockers* ; Calcium Channels* ; Calcium* ; Clinical Protocols ; Dizziness ; Drug Overdose ; Emergency Service, Hospital ; Extracorporeal Membrane Oxygenation* ; Humans ; Hyperlipidemias ; Hypotension ; Metformin* ; Oxidoreductases ; Receptors, Angiotensin ; Renal Replacement Therapy* ; Suicide ; Vomiting